Sublingual administration has an advantage for active substances which, when given orally, are subject to a substantial effect of first passage through the liver, resulting in rapid metabolization and a loss of therapeutic activity related to the activity of the liver enzymes that convert the molecule into inactive metabolites, or the activity of which is decreased because of this bioconversion.
In the case of sublingual administration, systemic passage is very rapid due to the considerable permeability and vascularization of the buccal mucosa. This makes it possible to obtain an effect which is more rapid than that obtained with oral administration. In the case of oral administration, in fact, the tablet is swallowed and systemic passage occurs only at the level of the gastrointestinal mucosa, i.e. later.
Moreover, sublingual administration can also allow the administration of active substances which are not normally absorbed at the level of the stomach mucosa or digestive mucosa after oral administration, or alternatively which are partially or completely degraded in acidic medium after ingestion of the tablet.
Fentanyl citrate is presently available in the form of a candy-on-a-handle (lollipop) for transmucosal administration which is marketed under the trade name Actiq®. The problem linked to this specific form is that the patient must keep the lollipop in the mouth for at least 15 minutes in order to obtain the desired amount of fentanyl. Furthermore, the amount of absorbed fentanyl is dependent of the frequency of saliva swallowing and thus very dependent of the patient. It is thus difficult to precisely check the absorbed amount of fentanyl.
For this reason, it is thought that formulation of fentanyl in the form of sublingual tablets would be better.
The sublingual tablets known from the prior art are usually prepared by direct compression of a mixture of powders comprising the active substance and compression excipients, such as diluents, binders, disintegrating agents and adjuvants.
In an alternative method of preparation, the active substance and the compression excipients can be dry- or wet-granulated beforehand.
In this case, the active substance is distributed throughout the mass of the tablet.
WO 00/16750 describes a tablet for sublingual use that disintegrates rapidly and comprises an ordered mixture in which the active substance is in the form of microparticles which adhere to the surface of water-soluble particles that are substantially greater in size, constituting a support for the active microparticles, the composition also comprising a mucoadhesive.
WO 00/57858 describes a tablet for sublingual use, comprising an active substance combined with an effervescent system intended to promote absorption, and also a pH modifier.
Sublingual administration is an administration route which has certain limits due to the size of the sublingual cavity in which the tablet is placed, to the limited volume of saliva for solubilizing the active substance or else to the limited amount of active substance that can cross the buccal mucosa.
Because of these limits, tablets in which the active substance is distributed uniformly within the mass of the tablet have certain drawbacks that the present invention aims to solve.
A first drawback of these tablets in which the active substance is dispersed within the mass is the dependency which exists between the size of the tablet and the dosage of the active substance. Thus, if it is intended to provide tablets of various dosages, it will be necessary to have tablets of various sizes.
It may therefore be that the size of the tablet containing the highest dose, in particular its diameter, is no longer suitable for sublingual administration.
This may force those skilled in the art to modify the formula of the tablet containing the highest dose, in particular so as to adapt its size to sublingual use, which means, in the end, having tablets with different qualitative and/or quantitative formulae for one and the same active substance, which is neither economically desirable, nor desirable in terms of safety.
Moreover, sublingual administration requires the use of an active substance of specific particle size, usually consisting of a population for which the diameter is less than 10 μm, preferably less than 5 μm, as measured by the usual techniques, for example by laser diffraction.
This choice is aimed at ensuring rapid and complete solubilization of said active substance in the saliva and allowing immediate and sufficient systemic passage so as to obtain an instantaneous effect.
Now, the use of particles of this size in tablets means that it is also necessary to adapt the particle size of the excipients constituting the mass of the tablet and to very precisely define the mixing parameters for the pulverulent mass, in order to obtain an ordered mixture in which the active substance is uniformly distributed, without witnessing the appearance of a segregation phenomenon in the feed hopper of the tablet press, which would be liable to compromise the uniformity of content of the tablets during the compression.
The risk of appearance of a segregation phenomenon is further increased when the unit dose of active substance in each tablet is low. This is, for example, the case with fentanyl, for which the unit dose is generally less than a milligram to a few milligrams.
It is then difficult to obtain an acceptable uniformity of content for the same batch throughout the compression step, the active substance then being highly diluted in the pulverulent mixture of excipients.
For tablets for sublingual administration in which the active substance is uniformly dispersed in the mass, the release of the active substance is also dependent upon the rate of disintegration of the tablet.
The prior art describes tablets that disintegrate rapidly, suitable for sublingual administration, in which the active substance is distributed within the mass of the tablet.
It is known that these tablets usually have a low hardness, often less than 40 N, and exhibit a tablet friability that is too great, so that they must be handled with care.
In the case of a tablet having a greater hardness, the disintegration is less rapid, so that the tablet erodes gradually while releasing the active substance from the surface of the tablet to its centre.
It is therefore particularly advantageous to have a formulation for sublingual administration that can rapidly release the active substance and allow immediate absorption thereof, without this release being dependent upon the rate of disintegration or upon the hardness of the tablet.
When the tablet is intended to disintegrate rapidly and without chewing, the disintegration leads to the formation of a pulp or of a suspension that can be unintentionally swallowed.
The viscosity of the pulp or suspension, which is related to the use of disintegrating agents or of swelling agents intended to accelerate the disintegration, can cause a swallowing reflex.
Consequently, part of the active substance is swallowed before being absorbed by the buccal mucosa.
The absorption at the level of the buccal mucosa, on which the bioavailability of the active substance directly depends, is therefore dependent upon the nature of the excipients used in this type of rapid disintegration formulation.
The Applicant has now demonstrated that, unexpectedly and surprisingly, it is possible to remedy these drawbacks by means of a solid unit form, in particular a coated tablet.